There is scattered evidence in the literature for the use of ultrasound in crystallization methodologies. By and large, ultrasound is used in crystallization methods to avoid metastable supersaturations (e.g., with highly viscous melts), to increase the formation of isometric crystals (e.g., adipic acid), and to micronize particle sizes (e.g., in precipitation processes). Such effects from the application of ultrasound in crystallization processes are thought to result from the occurrence of cavitation bubbles that, on collapse, give rise to microscopic water jets that may destroy agglomerates or enforce turbulent mixing in otherwise static diffusion layers around crystals. Until now there is no consistent meaningful model that accounts for all effects observed.
Although the chemical effects of ultrasound have been known for a long time, intensive modern study in this area only began at the beginning of the 1980s. Ultrasound can intensify the heat transfer, the nucleation rate (N. Enomoto et al., J. Mater. Sci. 27, 5239 (1992)) and the growth rate of crystals. Nucleation can be induced in a crystal-free solution below the supersaturation point at which primary nucleation would normally occur. Ultrasound can also generate substantial quantities of secondary nuclei. One mechanism involves cavitation, which tends to be focused at discontinuities in the liquid medium, and so takes place on or near the crystal surfaces. The intense forces of the collapse of cavitation bubbles can result in significant secondary nucleation. The mechanism by which ultrasound affects crystal growth is less well understood, but there may be a significant effect of acoustic streaming, providing enhanced mass transfer close to the crystal surface. More recently, it has been suggested that high-intensity sound initiates nucleation and helps to control crystal size and habit to yield products that better meet users' specifications (L. J. McCausland, Chem. Eng. Progress, pp. 56-61 (July 2001)).
In the pharmaceutical industry, there is a need for a low cost, efficient and effective large-scale method for reducing the particle size of pharmaceutically active ingredients. The particle size of a pharmaceutical ingredient may advantageously affect the properties of the ingredient, for example, by permitting preparation of dosage forms with improved dissolution or content uniformity.